Genetic Variant RUNX1:c.613+108G>A (chr21-34859366-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BP4BA1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.613+108G>A is a noncoding (intronic) variant. This variant has a MAF of 0.00244 (0.244%, 646/265052, 547 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort, which is ≥ 0.0015 (0.15%) (BA1). No splicing impact or creation of cryptic splice sites is predicted by SSF and MES. SpliceAI predicts no impact to splicing (score: 0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.18222 < 2.0) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014446/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0071 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00089 ( 5 hom. )

Consequence

RUNX1
NM_001754.5 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:3

Conservation

PhyloP100: -0.0830

Publications

0 publications found

Variant links:

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RUNX1 links:

RUNX1-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

RUNX1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RUNX1	NM_001754.5	MANE Select	c.613+108G>A	intron	N/A	NP_001745.2
RUNX1	NM_001001890.3		c.532+108G>A	intron	N/A	NP_001001890.1	Q01196-1
RUNX1	NM_001122607.2		c.532+108G>A	intron	N/A	NP_001116079.1	Q01196-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.613+108G>A	intron	N/A	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.613+108G>A	intron	N/A	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000344691.8	TSL:1	c.532+108G>A	intron	N/A	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes

AF:

0.00695

AC:

1058

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00190

AC:

444

AN:

233656

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000481

Gnomad OTH exome

AF:

0.000525

GnomAD4 exome

AF:

0.000893

AC:

705

AN:

789822

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

353

AN XY:

417470

show subpopulations

African (AFR)

AF:

0.0211

AC:

429

AN:

20332

American (AMR)

AF:

0.00145

AC:

AN:

41946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21216

East Asian (EAS)

AF:

0.000137

AC:

AN:

36556

South Asian (SAS)

AF:

0.00133

AC:

AN:

71698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52694

Middle Eastern (MID)

AF:

0.00179

AC:

AN:

4464

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

502882

Other (OTH)

AF:

0.00231

AC:

AN:

38034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00705

AC:

1074

AN:

152338

Hom.:

Cov.:

AF XY:

0.00693

AC XY:

516

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0241

AC:

1002

AN:

41578

American (AMR)

AF:

0.00327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00413

Hom.:

Bravo

AF:

0.00779

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.6

(source)

DANN

Benign

0.82

PhyloP100

-0.083

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over